The purpose of this research study is to learn more about the effects of using proton radiation therapy delivered over a shorter course of treatment (3 weeks) compared with a longer, standard course of treatment (5 weeks) for women with breast cancer who require radiotherapy to the breast/chest wall and regional lymph nodes.

This study is being done to see if comprehensive regional nodal radiation therapy to the breast or chest wall and regional lymph node area using proton therapy delivered with a hypofractionated approach (less treatment days) will result in rates of treatment related skin and soft tissue side effects that are non-inferior compared to conventionally fractionated proton radiotherapy regimens.

Inclusion Criteria:

• Patients with Stage I-III breast cancer who have undergone breast conserving surgery or mastectomy and have been recommended to receive postoperative radiation therapy to the breast or chest wall and regional draining lymph nodes (axilla levels I-III, SCV, IMN)
• Histologically documented breast cancer (invasive mammary, ductal, medullary, tubular, mucinous, lobular, or ductal carcinoma in situ) for which treatment with radiation therapy to the breast/chest wall and comprehensive regional lymph nodes including the internal mammary chain is recommended
• Documentation of negative metastatic workup by whole body Positron Emission Tomography - Computed Tomography (PET/CT) or by combined CT of the chest, abdomen, pelvis and Bone scan
• History and physical exam within 90 days prior to study registration
• Eastern Cooperative Oncology Group (ECOG) performance status 0, 1, or 2
• Negative pregnancy test for women of child-bearing potential
• Able to begin radiation treatment within 12 weeks of last surgery or last day of chemotherapy
• Presence of breast implants, breast expanders, tissue flap, or other breast reconstruction are allowed
• Bilateral breast cancer is allowed if at least one side will be treated with comprehensive nodal irradiation per protocol treatment and will be recorded as the laterality receiving comprehensive nodal irradiation. If both sides will be treated comprehensively, it will be documented as such

Exclusion Criteria:

• Presence of skin ulceration and / or ipsilateral satellite nodules and/or edema (including peau d'orange) (T4b or T4c disease) or diagnosis of inflammatory breast cancer (T4d disease)
• Residual gross disease detected by imaging or clinical exam with the exception of <2cm internal mammary lymph node or supraclavicular lymph node amenable to sequential boost
• Prior history of radiation therapy overlapping with current target volume (including intraoperative brachytherapy, interstitial catheter brachytherapy, balloon brachytherapy, external beam radiation therapy)
• Prior history of explant surgery or implant removal due to infection or wound healing issues without subsequent implant or flap reconstruction
• Presence of double/dual port tissue expander
• Clinical or radiographic evidence of distant metastatic disease
• Pregnant or breast-feeding females
• Non-malignant systemic disease that would preclude the patient from receiving study treatment or would prevent required follow-up
• History of connective tissue disorder (i.e., systemic lupus erythematosus, scleroderma), dermatomyositis, xeroderma pigmentosum
• Known BRCA 1 or BRCA 2 mutation
• Presence of an active skin rash
• Prior invasive non-study malignancy unless disease free for ≥ 3 years. Non-melanoma skin cancer, well-differentiated thyroid cancers, in situ carcinomas of the oral cavity, cervix, and other organs, and tumors that are not thought to impact the life expectancy of the patient are permissible.